Formulations comprising triptan compounds

ABSTRACT

The invention also provides a pharmaceutical composition for intranasal administration comprising a triptan, a pharmaceutically acceptable vehicle and a mucosal permeation enhancer, wherein upon said administration said composition provides a Tmax substantially equivalent to subcutaneous administration of said triptan. Other aspects and embodiments are contemplated and described.

INTRODUCTION

The present invention provides a pharmaceutical composition comprising asalt of sumatriptan or a pharmaceutically acceptable solvate thereof,and a mucosal permeation enhancer; their use for treating conditionsassociated with cephalic pain.

The current therapies to treat migraine headaches include theadministration of serotonin 5HT_(1B/1D) receptor agonists collectivelycalled as triptans, which chemically are tryptamine-based drugs.Sumatriptan was the first of these compounds to be developed, whichoffered improved efficacy and tolerability over ergot-derived compounds.The development of sumatriptan was quickly followed by a number ofsecond generation triptans including zolmitriptan, naratriptan, andrizatriptan. Recent polls of migraineurs (people who suffer frommigraines more than twice a month) suggest that more lipophilicformulations of other triptans, given orally, are still preferred overthe sumatriptan nasal spray (IMITREX®). While these alternative triptanshave slightly different binding affinities for the various 5H^(1B/1D)receptors, the single guiding factor in success with these formulationsseems to be the speed of action.

Sumatriptan is a selective 5-hydroxytryptamine ID (5-HT_(1D)) receptoragonist useful for treatment of migraine. Sumatriptan has a chemicalname 1-[3-(2-dimethylaminoethyl)-1H-indole-5-yl]-N-methyl-methanesulphonamide, which has the following structure (I). Broadly, all thetriptans are selective 5HT receptor agonists useful for treatment ofmigraine.

U.S. Pat. No. 5,705,520 describes 3-[2-(dimethylamino)ethyl]-N-methyl-1H-methanesulphonamide sulphate salt (2:1) andpharmaceutically acceptable solvates thereof, and pharmaceuticalcompositions containing the compound. The compound is useful in thetreatment of conditions associated with cephalic pain, in particularmigraine. The pharmaceutical compositions are particularly useful asintranasal formulations.

U.S. Pat. No. 5,554,639 discloses 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide sulphate salt (2:1) andpharmaceutically acceptable solvates thereof. The compound is of use inthe preparation of pharmaceutical compositions for use in the treatmentof conditions associated with cephalic pain, in particular migraine,wherein an aqueous solution has a pH range of 5 to 7.

U.S. Patent Application Publication No. 2007/0298010 disclosesalkylglycoside-containing compositions and methods for increasing thestability, reducing the aggregation and immunogenicity, increasing thebiological activity, and reducing or preventing fibrillar formation of apeptide, polypeptide, or variant thereof, for example insulin, PeptideT, or analogs thereof.

International Application No. WO 2006/025882 discloses a compositionincluding a surfactant, at least one alkyl glycoside and/or saccharidealkyl ester, and a drug. The surfactant compositions when admixed with adrug are non-toxic and non-irritating, while stabilizing and increasingthe bioavailability of the drug. The invention also providescompositions that enhance absorption of drugs via oral, ocular, nasal,nasolacrimal, inhalation, pulmonary, oral cavity (sublingual or buccal)or CSF delivery route of a patient. The drugs include glucagon andexendin-4.

Pharmaceutical preparations containing sumatriptan or salts ofsumatriptan are described in U.S. Pat. Nos. 4,816,470, 4,994,483,5,037,845, 5,270,333, 5,288,498, 5,307,953, 5,393,773, 5,447,729,5,554,639, 5,705,520, 5,863,559, 6,020,001, 6,255,502, 6,294,192, and6,368,627, U.S. Patent Application Publication Nos. 2003/0013753,2003/0185761, and 2003/0190286, International Application PublicationNos. WO 98/02186 and WO 01/39836, and German Patent No. 4314976.

Great Britain Patent Specification No. 2162522 describes physiologicallyacceptable salts of3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methane sulphonamide(sumatriptan), which are the succinate, hemisuccinate, fumarate,benzoate, methanesulphonate, and hydrochloride salts.

U.S. Patent Application Publication No. 2006/002989 disclosespharmaceutical compositions comprising sumatriptan succinate and sodiumcaprate for increased absorption of sumatriptan succinate acrossbiological membranes. The invention is also directed to methods ofmaking the pharmaceutical compositions and uses thereof.

Commercially, sumatriptan nasal products sold under the trade nameIMITREX®, supplied as a nasal spray containing 5, 10 or 20 mg ofsumatriptan in a 100 μL unit dose aqueous buffered solution containingmonobasic potassium phosphate NF, anhydrous dibasic sodium phosphateUSP, sulfuric acid NF, sodium hydroxide NF, and purified water USP. ThepH of the solution is approximately 5.5. The osmolality of the solutionis 372 or 742 m-Osmol for the 5 and 20 mg nasal sprays.

The existing marketed formulations of triptans have onset of actionabout 30 minutes or less. Thereby It is highly desirable to develop aformulation where there would be a onset of action quicker than existingformulation, after dosing, so that there will be faster relief of painin migraine.

There is a long felt need to develop alternate triptan formulations thathave an increased speed or onset of action as well as an improvedpermeability over the earlier triptan formulations and meeting the unmetrequirements in the treatment of migraine attacks.

SUMMARY

The present invention provides a pharmaceutical composition comprising asalt of sumatriptan or a physiologically acceptable solvate thereof, amucosal permeation enhancer and optionally at least one pharmaceuticallyacceptable excipient, wherein the said composition provides T_(max)value of less than 30 minutes upon said administration.

The present invention provides a pharmaceutical composition comprising asalt of sumatriptan or a physiologically acceptable solvate thereof, analkylglycoside or saccharide alkyl ester and optionally at least onepharmaceutically acceptable excipient, wherein the said compositionprovides T_(max) value of less than 30 minutes upon said administration.

Preferably, an aspect of the present invention specifically provides apharmaceutical composition comprising a citrate salt of sumatriptan or aphysiologically acceptable solvate thereof, an alkylglycoside orsaccharide alkyl ester, and optionally at least one pharmaceuticallyacceptable excipient.

In another aspect the present invention provides a method of treating ahuman suffering from or susceptible to cephalic pain which comprisesadministration of a composition comprising a salt of sumatriptan or aphysiologically acceptable solvate thereof, an alkyl glycoside orsaccharide alkyl ester and optionally at least one pharmaceuticallyacceptable excipient, wherein the said composition provides T_(max)value of less than 30 minutes upon said administration.

Another aspect of the invention provides a pharmaceutical compositionfor intranasal administration comprising a triptan, a pharmaceuticallyacceptable vehicle and a mucosal permeation enhancer, wherein upon saidadministration said composition provides a T_(max) substantiallyequivalent to subcutaneous administration of said triptan.

Another aspect of the invention provides a method of treating ormitigating diseases or conditions suitable for treatment with triptancompounds in a subject in need thereof, said method comprisingintranasally administering to said subject a pharmaceutical compositioncomprising a triptan, a pharmaceutically acceptable vehicle and amucosal permeation enhancer, wherein upon said administration, saidcomposition provides a T_(max) substantially equivalent to subcutaneousadministration of said triptan.

Another aspect of the invention provides a method of treating ormitigating diseases or conditions suitable for treatment with triptancompounds in a subject in need thereof, said method comprisingintranasally administering to said subject a pharmaceutical compositioncomprising a triptan, a pharmaceutically acceptable vehicle and amucosal permeation enhancer, wherein upon said administration, saidcomposition provides i) a C_(max) at a time T_(max), ii) C_(max2) at atime T_(max2), iii) a C_(min) at a time of T_(min) and iv) a ratio ofC_(max2) to AUC_(Tmin-inf), said T_(min) being later than said T_(max)and earlier than said T_(max2), said C_(max) and said T_(max) beingcharacteristic of subcutaneous administration and said AUC_(Tmin-inf)being characteristic of intranasal administration without said mucosalpermeation enhancer.

DESCRIPTION OF DRAWINGS

FIG. 1 shows a comparison of the average plasma levels of all patientsat the various time points as indicated for the Imitrex® nasal sprayreference and Phosphate salt of Sumatriptan pharmaceutical compositiondescribed herein.

FIG. 2 shows a comparison of the average plasma levels of all patientsat the various time points as indicated for the Imitrex® nasal sprayreference and Citrate salt of Sumatriptan pharmaceutical compositiondescribed herein.

FIG. 3 shows a comparison of the average plasma levels of all patientsat the various time points as indicated for the Imitrex® nasal sprayreference and Sulphate salt of Sumatriptan pharmaceutical compositiondescribed herein.

FIG. 4 shows a comparison of the average plasma concentration of allpatients at various time points as indicated for the Imitrex® nasalspray reference and Sulphate salt of Sumatriptan (Sulphate) uponintranasal administration of the pharmaceutical formulation comprising0.1%, 0.15% & 2.0% concentrations of Permeation Enhancer (PE)respectively’.

DETAILED DESCRIPTION Definitions

‘Salt of sumatriptan’ is intended to include, but not limited to, any ofthe following salts of sumatriptan: sulphate salt, citrate salt,phosphate salt, maleate salt, formate salt and acetate salt.

Other examples of salts of sumatriptan are, but not limited to,hydrochloride, hydrobromide, nitrate, mesylate, benzoate and succinate.

‘Salt of sumatriptan’ is also intended to include above defined salt ofSumatriptan formed either externally or in situ during the preparationof the composition, by addition of the corresponding acid.

‘Salts or a derivative of citric acid’ indicates a source of citric acidthat can be selected from the group containing citric acid anhydrous,citric acid monohydrate, trisodium citrate dihydrate, monosodium citrateand citric acid solutions.

‘Commercial formulation’ means ‘Imitrex® (Sumatriptan) nasal spray, 20mg per 100 microliters), manufactured by GlaxoSmithKline’,‘Physiologically acceptable solvates’ includes ‘their hydrates thereof’as well.

‘Quantity sufficient’ can be defined as the minimum amount of thesolvent required for dissolving the active ingredient.

‘Triptan’ includes sumatriptan, rizatriptan, naratriptan, zolmitriptan,eletriptan, almotriptan, frovatriptan and/or a pharmaceuticallyacceptable salt, solvate, hydrate, polymorph, prodrug or mixturesthereof.

‘Area under the curve’ or “AUC” is the area as measured under a plasmadrug concentration curve. Often, the AUC is specified in terms of thetime interval across which the plasma drug concentration curve is beingintegrated, for instance AUC_(start-finish). Thus, AUC₀₋₂₄ refers to theAUC obtained from integrating the plasma concentration curve over aperiod of zero to 24 hours, where zero conventionally represents thetime of administration of the drug or dosage form thereof to a patient.

AUC₀₋₂ refers to the AUC obtained from integrating the plasmaconcentration curve over a period of zero to 2 hours, where zeroconventionally represents the time of administration of the drug ordosage form thereof to a patient. AUC₀₋₆ refers to the AUC obtained fromintegrating the plasma concentration curve over a period of zero to 6hours, where zero conventionally represents the time of administrationof the drug or dosage form thereof to a patient. AUC_(t) refers to areaunder the plasma concentration curve from hour “0” to the lastdetectable concentration at time “t”, calculated by the trapezoidalrule. AUC_(inf) refers to the AUC value extrapolated to infinity,calculated as the sum of AUC_(s) and the area extrapolated to infinity,calculated by the concentration at time t (Ct) divided by K_(el). (Ifthe t_(1/2) value was not estimable for a subject, the mean t_(1/2)value of that treatment was used to calculate AUC_(inf)). “Mean, singledose, area under a plasma concentration-time curve AUC_(inf)” means themean AUC_(inf) obtained over several patients or by multipleadministrations to the same patient on different occasions withsufficient washout in between dosings to allow drug levels to subside topre-dose levels, following a single administration of a dosage form toeach patient. “Partial AUC” means area under the curve specified interms of the time interval across which the plasma drug concentrationcurve is being integrated, for instance AUC_(0-Tmax).

‘C’ means the concentration of drug in blood plasma, or serum, of asubject, generally expressed as mass per unit volume, typicallynanograms (ng) per milliliter. For convenience, this concentration maybe referred to herein as “drug plasma concentration”, “plasma drugconcentration” or “plasma concentration”. The plasma drug concentrationat any time following drug administration is referenced as C_(time), asin C_(9 h) or C_(24 h), etc. A maximum plasma concentration obtainedfollowing administration of a dosage form obtained directly from theexperimental data without interpolation is referred to as C_(max). Theaverage or mean plasma concentration obtained during a period ofinterest is referred to as C_(avg) or C_(mean). “Mean, single dose,maximum plasma concentration C_(max)” means the mean C_(max) obtainedover several patients or multiple administrations to the same patientwith sufficient washout in between dosings to allow drug levels tosubside to pre-dose levels etc., following a single administration of adosage form to each patient.

C_(max2) denotes a second maximum of concentration of drug in bloodplasma, or serum, of a subject, generally expressed as mass per unitvolume, typically nanograms (ng) per milliliter that occurs at timeafter administration later than C_(max).

‘C_(min)’ means the minimum concentration of drug in blood plasma, orserum, of a subject, generally expressed as mass per unit volume,typically nanograms (ng) per milliliter that occurs between C_(max) andC_(max2).

‘T_(min)’ is the time after administration of the drug when the drugconcentration has value of C_(min).

AUC_(Tmin-inf) refers to area under the plasma concentration curve from‘T_(min)’ to infinity. Here AUC_(inf) refers to the AUC valueextrapolated to infinity, calculated as the sum of AUC_(Tmin-t) and thearea extrapolated to infinity, calculated by the concentration at time t(Ct) divided by K_(el).

‘Mean, single dose, time to maximum plasma concentration T_(max)’ is themean time elapsed from administration to a patient of a dosage formcomprising a drug to the time at which the C_(max) for that drug isobtained over several patients or multiple administrations to the samepatient to the same patient with sufficient washout in between dosingsto allow drug levels to subside to pre-dose levels, etc., following asingle administration of the dosage form to each patient, and obtaineddirectly from the experimental data without interpolation.

‘Plasma drug concentration curve’ or ‘drug plasma concentration curve’,or “plasma concentration curve” or “plasma profile” or “plasmaconcentration profile” refer to the curve obtained by plotting plasmadrug concentration or drug plasma concentration, or plasma concentrationversus time. Usually, the convention is that the zero point on the timescale (conventionally on the X-axis) is the time of administration ofthe drug or dosage form comprising the drug to a patient.

The term ‘pharmaceutically acceptable excipient’ is used to describe asubstance which does not have inherent pharmacological activity and isused as an inactive ingredient.

‘Mucosal permeation enhancer’ denotes any penetration enhancer thatassists in penetration of the drug via mucosal membrane. It includes,but not limited to, alkylglycoside or saccharide alkyl ester.

The term ‘substantially equivalent to subcutaneous administration’ meansthat one skilled in the art of pharmacology and/or pharmacokineticswould recognize the shape and time profile of the blood/concentrationcurve as having characteristics of subcutaneous administration of thedrug.

The term ‘about’ denotes a range of value ranging from −10% of the valueit modifies to +10% of the value it modifies, with the proviso that suchclaim construction does not preclude application of broader equivalentvalues.

The term ‘alkylglycoside or saccharide alkyl ester’ includes, but is notlimited to, dodecyl maltoside (1-O-n-Dodecyl-(3-D-Maltopyranoside),tridecyl maltoside, sucrose monododecanoate, sucrose monotridecanoate,and sucrose monotetradecanoate.

In general, alkylglycosides or saccharide alkyl esters useful in thepresent invention include, but are not limited to: alkyl glycosides,such as octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-,tetradecyl-, pentadecyl-, hexadecyl-, heptadecyl-, andoctadecyl-[alpha]- or [beta]-D-maltoside, -glucoside or -sucroside(synthesized according to Koeltzow and Urfer; Anatrace Inc., Maumee,Ohio; Calbiochem, San Diego, Calif.; Fluka Chemie, Switzerland); alkylthiomaltosides, such as heptyl, octyl, dodecyl-, tridecyl-, andtetradecyl-[beta]-D-thiomaltoside (synthesized according to Defaye, J.and Pederson, C, “Hydrogen Fluoride, Solvent and Reagent forCarbohydrate Conversion Technology” in Carbohydrates as Organic RawMaterials, 247-265 (F. W. Lichtenthaler, ed.) VCH Publishers, New York(1991); Ferenci, T., J. Bacteriol, 144:7-1 1 (1980)); alkylthioglucosides, such as heptyl- or octyl 1-thio [alpha]-or[beta]-D-glucopyranoside (Anatrace, Inc., Maumee, Ohio; see Saito, S.and Tsuchiya, T. Chem. Pharm. Bull. 33:503-508 (1985)); alkylthiosucroses (synthesized according to, for example, Binder, T. P. andRobyt, J. F., Carbohydr. Res. 140:9-20 (1985)); alkyl maltotriosides(synthesized according to Koeltzow and Urfer); long chain aliphaticcarbonic acid amides of sucrose [beta]-amino-alkyl ethers; (synthesizedaccording to Austrian Patent 382,381 (1987); derivatives of palatinoseand isomaltamine linked by amide linkage to an alkyl chain (synthesizedaccording to Kunz, M., “Sucrose-based Hydrophilic Building Blocks asIntermediates for the Synthesis of Surfactants and Polymers” inCarbohydrates as Organic Raw Materials, 127-153); derivatives ofisomaltamine linked by urea to an alkyl chain (synthesized according toKunz); long chain aliphatic carbonic acid ureides of sucrose[beta]-amino-alkyl ethers (synthesized according to Gruber and Greber,pp. 95-116); and long chain aliphatic carbonic acid amides of sucrose[beta]-amino-alkyl ethers (synthesized according to Austrian Patent No.382,381 (1987), Chemical Abstracts, 108: 1 14719 (1988) and Gruber andGreber, pp. 95-116). Surfactants of the alkylglycoside and/or sucroseester types have characteristic hydrophilic-lipophilic balance (HLB)numbers, which can be calculated or determined empirically (M. J.Schick, Nonionic Surfactants, Marcel Dekker, Inc., New York, p. 607,1967). Examples of suitable penetration enhancers are also disclosed inUS20060046962, US20060045869, US20060045868, US20090163447,US20090047347, US20080299079, US20080200418, US20060046969, which areincorporated herein by reference in their entirety and for the purposestated.

Absorption and permeation of a drug involves passage of the drug acrossbiological membranes whereby a cell, tissue or organ takes up the drug.Absorption/permeation is also referred to as the rate and extent towhich a drug leaves its site of administration. The physicochemicalproperties of the molecules in the pharmaceutical composition as well asthat of the membranes affect the absorption of drugs across membranes.

Biological membranes are sheets of tissue that include but are notlimited to membranes that provide a pliable surface lining forprotecting or partitioning organs and structures in the body. As usedherein, a biological membrane is an epithelial membrane. Epithelialmembranes include but are not limited to coverings or linings of theouter layer of skin and some internal organs, e.g., digestive,respiratory, reproductive and urinary systems. Epithelial membranesinclude the lining of body cavities.

Epithelial membranes include but are not limited to oral, buccal,sublingual, gingival, palatal, nasal, nasopharynxal, oropharynxal,conjunctival, transdermal, vaginal, and gastrointestinal membranes. Inone embodiment of the invention, the epithelial membrane is the nasalmembrane.

Absorption/permeation enhancers are agents that increase drug absorptionand permeation across biological membranes. Absorption/permeationenhancers for use in pharmaceutical composition of the present inventioninclude alkylglycosides but are not limited to alkylglycosides only;enhancers also may be materials such as sodium caprate, sodiumcaprylate, sodium laurate, sodium lauryl sulphate, and combinationsthereof.

The term ‘transmucosal’ relates to a delivery system through mucosa, themucosa may be of oral, buccal, sublingual, gingival, palatal, nasal,nasopharynxal, oropharynxal, conjunctival, vaginal, and gastrointestinalmembranes.

Therapeutically effective amounts of active ingredient can be providedin the form of a pharmaceutical composition in the form of suspensions,emulsions, solutions, aerosols, powders, and the like. All suchformulations are included herein without limitation.

The present invention provides a pharmaceutical composition comprising asalt of sumatriptan or a physiologically acceptable solvate thereof, amucosal permeation enhancer and optionally at least one pharmaceuticallyacceptable excipient, wherein the said composition provides T_(max)value of less than 30 minutes upon said administration.

The present invention provides a pharmaceutical composition comprising asalt of sumatriptan or a physiologically acceptable solvate thereof, analkylglycoside or saccharide alkyl ester and optionally at least onepharmaceutically acceptable excipient, wherein the said compositionprovides T_(max) value of less than 30 minutes upon said administration.

Preferably, according to the above aspect, the present inventionprovides a pharmaceutical composition comprising a sulphate salt ofsumatriptan or a physiologically acceptable solvate thereof, analkylglycoside or saccharide alkyl ester and optionally at least onepharmaceutically acceptable excipient.

Preferably, according to the above aspect, the present inventionprovides a pharmaceutical composition comprising a citrate salt ofsumatriptan or a physiologically acceptable solvate thereof, analkylglycoside or saccharide alkyl ester and optionally at least onepharmaceutically acceptable excipient.

Preferably, according to the above aspect, the present inventionprovides a pharmaceutical composition comprising a phosphate salt ofsumatriptan or a physiologically acceptable solvate thereof, analkylglycoside or saccharide alkyl ester and optionally at least onepharmaceutically acceptable excipient.

Preferably, according to the above aspect, the present inventionprovides a pharmaceutical composition comprising a maleate salt ofsumatriptan or formate salt of sumatriptan or acetate salt ofsumatriptan, or a physiologically acceptable solvate thereof, analkylglycoside or saccharide alkyl ester, and optionally at least onepharmaceutically acceptable excipient.

According to the above aspect, the present invention provides apharmaceutical composition comprising a salt of sumatriptan or aphysiologically acceptable solvate thereof, an alkylglycoside orsaccharide alkyl ester, and optionally at least one pharmaceuticallyacceptable excipient, the composition being adjusted to have a pH in therange of about 4 to about 8.

According to the above aspect, the present invention provides apharmaceutical composition comprising a salt of sumatriptan or aphysiologically acceptable solvate thereof, an alkylglycoside orsaccharide alkyl ester, and optionally at least one pharmaceuticallyacceptable excipient, the composition being adjusted to have a pH in therange of about 4.5 to about 7.5.

According to the above aspect, the present invention provides apharmaceutical composition comprising a salt of sumatriptan or aphysiologically acceptable solvate thereof, an alkylglycoside orsaccharide alkyl ester, and optionally at least one pharmaceuticallyacceptable excipient, the composition being adjusted to have a pH in therange of about 7.1 to about 9.

In the above aspect, C_(max) values ranges from about 14 to about 214ng/mL.

Preferably, according to the above aspect, the present inventionspecifically provides a pharmaceutical composition comprising a citratesalt of sumatriptan or a physiologically acceptable solvate thereof, analkylglycoside or saccharide alkyl ester, and optionally at least onepharmaceutically acceptable excipient, the composition being adjusted tohave a pH in the range of about 4 to about 8.

Preferably, according to the above aspect, the present inventionprovides a pharmaceutical composition comprising a citrate salt ofsumatriptan or a physiologically acceptable solvate thereof, analkylglycoside or saccharide alkyl ester, and optionally at least onepharmaceutically acceptable excipient, the composition being adjusted tohave a pH in the range of about 4.5 to about 6.5.

Preferably, according to the above aspect, the present inventionspecifically provides a pharmaceutical composition comprising aphosphate salt of sumatriptan or a physiologically acceptable solvatethereof, an alkylglycoside or saccharide alkyl ester, and optionally atleast one pharmaceutically acceptable excipient, the composition beingadjusted to have a pH in the range of about 4.5 to about 8.

Preferably, according to the above aspect, the present inventionspecifically provides a pharmaceutical composition comprising a sulphatesalt of sumatriptan or a physiologically acceptable solvate thereof, analkylglycoside or saccharide alkyl ester, and optionally at least onepharmaceutically acceptable excipient, the composition being adjusted tohave a pH in the range of about 4.5 to about 8.

Preferably, the above composition is adjusted to a pH in the range ofabout 5 to about 6.

In the above aspect, said mucosal permeation enhancer is present in aconcentration of from about 0.02 to about 3.0%.

Preferably, in the above aspect, said mucosal permeation enhancer ispresent in a concentration of from about 0.05 to about 2.5%.

Preferably, in the above aspect, said mucosal permeation enhancer ispresent in a concentration of from about 0.1 to about 2.0%.

An aspect of the present invention provides a pharmaceutical compositioncomprising a salt of sumatriptan or a physiologically acceptable solvatethereof, dodecyl maltoside, and optionally at least one pharmaceuticallyacceptable excipient.

In the above aspect, the said composition provides T_(max) value of lessthan 30 minutes upon said administration.

In the above aspect, the said composition provides T_(max) value of lessthan or equal to 15 minutes upon said administration.

An aspect of the present invention provides transmucosal formulationscomprising a salt of sumatriptan or a physiologically acceptable solvatethereof, an alkylglycoside or saccharide alkyl ester, and optionally atleast one pharmaceutically acceptable excipient.

In the above aspect, the said composition provides T_(max) value of lessthan 30 minutes upon said administration.

In the above aspect, the said composition provides T_(max) value of lessthan or equal to 15 minutes upon said administration.

An aspect of the invention provides a pharmaceutical compositioncomprising a salt of sumatriptan or a physiologically acceptable solvatethereof, an alkylglycoside or saccharide alkyl ester, and optionally atleast one pharmaceutically acceptable excipient, for delivery by thenasal route.

In the above aspect, the said composition provides T_(max) value of lessthan 30 minutes upon said administration.

In the above aspect, the said composition provides T_(max) value of lessthan or equal to 15 minutes upon said administration.

An aspect of the present invention provides a pharmaceutical compositioncomprising a salt of sumatriptan or a physiologically acceptable solvatethereof, an alkylglycoside or saccharide alkyl ester, and optionally atleast one pharmaceutically acceptable excipient, for delivery by thesubcutaneous route.

In the above aspect, the said composition provides T_(max) value of lessthan 30 minutes upon said administration.

In the above aspect, the said composition provides T_(max) value of lessthan or equal to 15 minutes upon said administration.

In the above aspect the salt of sumatriptan or a physiologicallyacceptable solvate thereof, is preferably sulphate salt, citrate salt orphosphate salt of sumatriptan or a physiologically acceptable solvatethereof, an alkylglycoside or saccharide alkyl ester, and optionally atleast one pharmaceutically acceptable excipient, wherein the compositionupon nasal administration shows the following one or morepharmacokinetic parameters:

-   -   T_(max) value of less than or equal to about 15 minutes, and/or    -   at least three fold reduction in T_(max) values when compared        with that of commercial formulation, and/or    -   at least three fold increase in C_(max) value when compared with        that of commercial formulation, and/or    -   at least one fold reduction in AUC_(0-Tmax) value when compared        with that of commercial formulation, and/or    -   at least one fold increase in AUC_(0-Tmax) value when compared        with that of similar composition comprising sulphate salt,        and/or    -   at least one fold increase in AUC_(0-inf) value when compared        with that of commercial formulation, and/or    -   the ratio of C_(max) to AUC_(0-inf) is at least about 0.3.

In one aspect the composition comprising citrate salt of sumatriptan ora physiologically acceptable solvate thereof, an alkylglycoside orsaccharide alkyl ester, and optionally at least one pharmaceuticallyacceptable excipient wherein the composition upon nasal administrationshows the T_(max) value of less than or equal to about 15 minutes.

Another aspect of the present invention provides a method of treatingmigraine attacks by nasal administration of the formulation comprising asumatriptan salt or its physiologically acceptable solvate thereof andat least about 0.1% of alkyl glycoside.

In the above aspect, the alkyl glycoside is selected from dodecylmaltoside, tridecyl maltoside, tetradecyl maltoside, octyl decyl alphaor beta maltoside.

Preferably, the salt of sumatriptan is citrate salt.

Preferably, the salt of sumatriptan is phosphate salt.

Preferably, the salt of sumatriptan is sulphate salt.

In another aspect the present invention provides a method of treating ahuman suffering from or susceptible to cephalic pain which comprisesadministration of a composition comprising a salt of sumatriptan or aphysiologically acceptable solvate thereof, an alkyl glycoside orsaccharide alkyl ester and optionally at least one pharmaceuticallyacceptable excipient.

In the above aspect, the said composition provides T_(max) value of lessthan 30 minutes upon said administration.

In the above aspect, the said composition provides T_(max) value of lessthan or equal to 15 minutes upon said administration.

In the above method, the composition was adjusted to a pH in the rangeof about 4 to about 8, preferably about 4.5 to about 7.5.

Yet another aspect of the present invention provides a method oftreating a human suffering from or susceptible to cephalic pain whichcomprises administration of a composition comprising citrate salt ofsumatriptan or a physiologically acceptable solvate thereof, an alkylglycoside or saccharide alkyl ester and optionally at least onepharmaceutically acceptable excipient.

In the above aspect, the said composition provides T_(max) value of lessthan 30 minutes upon said administration.

In the above aspect, the said composition provides T_(max) value of lessthan or equal to 15 minutes upon said administration.

In the above method, the composition is adjusted to a pH in the range ofabout 4 to about 8, preferably about 4.5 to about 6.5, still furtherpreferably about 5 to about 6.

In an aspect, the present invention provides transmucosal formulationscomprising a salt of sumatriptan or a pharmaceutically acceptablesolvates thereof. In an embodiment, the invention provides sumatriptanpharmaceutical composition comprising sumatriptan or a pharmaceuticallyacceptable salt, solvate, hydrate, polymorph, prodrug or mixturesthereof, and an alkylglycoside. One embodiment also includes processesfor preparing such formulations and method of using such formulationsfor treating conditions associated with cephalic pain in mammals,specifically migraine.

An aspect of the present invention provides a transmucosal deliverysystem comprising a salt of sumatriptan or a physiologically acceptablesolvate thereof, and a mucosal permeation enhancer.

An aspect of the present invention provides intranasal delivery systemscomprising a salt of sumatriptan or a physiologically acceptable solvatethereof, and a mucosal permeation enhancer. The intranasal compositionmay be provided in a liquid form or in the form of dry powder. Theliquid form can be solutions applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or a spray or assolutions using pressurized metered-dose inhalers (pMDI), or as drypowders using dry powder inhaler devices (DPIs). Alternatively theformulation may also be administered by breath actuated inhalers (BD's).The dry powder form can be a spray dried composition or a freeze driedcomposition having the drug in a micronized form and alternatively thedrug can be in a microparticulate or a nanoparticulate form.

Further aspect of the present invention provides intranasal deliverysystems comprising a salt of sumatriptan or a physiologically acceptablesolvate thereof, and a mucosal permeation enhancer.

Further aspect of the invention provides compositions comprising a saltof sumatriptan, wherein the composition is formulated for administrationinto the circulatory system of a subject via the oral, ocular,nasolacrimal, inhalation, pulmonary, sublingual, buccal or CSF deliveryroute.

An aspect of the present invention provides an aerosol formulationcomprising a salt of sumatriptan or a physiologically acceptable solvatethereof, and a mucosal permeation enhancer as a solution in a propellantadministered using pressurized metered-dose inhalers (pMDI) or by breathactuated inhalers (BDIs).

In the present invention, the inventors have surprisingly found that theuse of a mucosal permeation enhancer in the pharmaceutical compositioncomprising a salt of sumatriptan or a physiologically acceptable solvatethereof, increases permeation through mucosa to enhance drug absorption,and provides an improved pharmacokinetic profile with simultaneousimprovement in the onset of action and enhanced residence time whichcould facilitate more amounts of drug exposure to the absorption site,thus a possibility of enhanced absorption and improved bioavailability.

In a further aspect, the invention provides the use of a salt ofsumatriptan or a physiologically acceptable solvate thereof, in thepreparation of a medicament for use in the treatment of conditionsassociated with cephalic pain such as cluster headache, chronicparoxysmal hemi-crania, headache associated with vascular disorders,headache associated with substances or their withdrawal (for exampledrug withdrawal), tension headache, and in particular, migraine.

In another embodiment, a pharmaceutical composition comprising a salt ofsumatriptan or a physiologically acceptable solvate thereof and analkylglycoside or saccharide alkyl ester adapted for intranasaladministration will be in the form of an aqueous solution.

In another embodiment a pharmaceutical composition comprising salt ofsumatriptan or a physiologically acceptable solvate thereof and analkylglycoside or saccharide alkyl ester adapted for intranasaladministration will be in the powder form.

In the above embodiment, the salt is selected from sulphate, phosphate,citrate, maleate, formate, acetate or succinate.

In the above embodiment the salt is preferably citrate salt.

In the above embodiment the salt is preferably phosphate salt.

In the above embodiment the salt is preferably sulphate salt.

Another aspect of the invention provides a pharmaceutical compositionfor intranasal administration comprising a triptan, a pharmaceuticallyacceptable vehicle and a mucosal permeation enhancer, wherein upon saidadministration said composition provides a T_(max) substantiallyequivalent to subcutaneous administration of said triptan.

In one embodiment of the above aspect of the invention, the mucosalpermeation enhancer is not a cyclodextrin.

In the above aspect, said mucosal permeation enhancer is present in aconcentration of from about 0.02 to about 3.0%.

Preferably, in the above aspect, said mucosal permeation enhancer ispresent in a concentration of from about 0.05 to about 2.5%.

Preferably, in the above aspect, said mucosal permeation enhancer ispresent in a concentration of from about 0.1 to about 2.0%.

In the above aspect, said T_(max) ranges from about 4 to about 15minutes.

Specifically contemplated is a formulation for intranasal administrationand related method of administration which provides biphasicblood/concentration curve.

In accordance with the above aspect, said composition provides aC_(max2) at a time of T_(max2), said T_(max2) being later than saidT_(max).

In the above aspect, said composition provides a C_(min) at a time ofT_(min), said T_(min) being later than said T_(max) and earlier thansaid T_(max2).

In the above aspect, said T_(max) ranges from about 4 to about 15minutes.

In accordance with the above aspect, said mucosal permeation enhancer isalkyl glycoside or saccharide alkyl ester.

In the above aspect, said alkyl glycoside or saccharide alkyl ester isselected from (1-O-n-Dodecyl-β-D-Maltopyranoside), tridecyl maltoside,sucrose monododecanoate, sucrose monotridecanoate and sucrosemonotetradecanoate.

Examples of suitable penetration enhancers are disclosed inUS20060046962, US20060045869, US20060045868, US20090163447,US20090047347, US20080299079, US20080200418, US20060046969, which areincorporated herein by reference for the purpose stated.

In the above aspect, said triptan compound is sumatriptan, apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate thereof.

In the above aspect, said pharmaceutical composition provides i) aC_(max) at a time T_(max), ii) C_(max2) at a time T_(max2), iii) aC_(min) at a time of T_(min), and iv) a ratio of C_(max2) toAUC_(Tmin-inf), said T_(min) being later than said T_(max) and earlierthan said T_(max2), said C_(max) and said T_(max) being characteristicof subcutaneous administration and said AUC_(Tmin-inf) beingcharacteristic of intranasal administration without said mucosalpermeation enhancer.

In the above aspect, T_(max) ranges from about 4 to about 15 minutes.

In the above aspect, T_(max2) ranges from about 30 to about 120 minutes.

In the above aspect, C_(max) ranges from about 14 to about 214 ng/mL.

In the above aspect, C_(max2) ranges from about 9 to about 80 ng/mL.

In the above aspect, said pharmaceutically acceptable vehicle is aliquid.

In the above aspect, said pharmaceutically acceptable vehicle is a drypowder, or a mixture of dry powder with a liquid. Examples of suitablepropellants are described, for example, U.S. Pat. Nos. 7,718,162, and7,459,146, which are incorporated herein by reference in their entiretyand for the purpose stated. Any suitable device may be used forintranasal administration of the compositions described herein. Methodsfor selecting suitable delivery devices are described, for example, IU.S. Pat. No. 7,659,725, which is incorporated herein by reference inits entirety and for the purpose stated.

The pharmaceutically acceptable vehicle may also be a liquid orpressurized liquid. Any device known in the art for intranasaladministration may be used to deliver the pharmaceutical composition ofthe present invention. An example of suitable device is described inU.S. Pat. No. 7,497,214, which is incorporated herein by reference forthe purpose stated.

Yet another aspect of the invention provides a method of treating ormitigating diseases or conditions suitable for treatment with triptancompounds in a subject in need thereof, said method comprisingintranasally administering to said subject a pharmaceutical compositioncomprising a triptan, a pharmaceutically acceptable vehicle and amucosal permeation enhancer, wherein upon said administration, saidcomposition provides a T_(max) substantially equivalent to subcutaneousadministration of said triptan.

In the above aspect said T_(max) ranges from about 4 to about 15minutes.

In the above aspect, said composition provides a C_(max2) at a time ofT_(max2), said T_(max2) being later than said T_(max).

In the above aspect, said composition provides a C_(min) at a time ofT_(min), said T_(min) being later than said T_(max) and earlier thansaid T_(max2).

In the above aspect, said mucosal permeation enhancer is alkyl glycosideor saccharide alkyl ester.

In the above aspect, said alkyl glycoside or saccharide alkyl ester isselected from (1-O-n-Dodecyl-β-D-Maltopyranoside), tridecyl maltoside,sucrose monododecanoate, sucrose monotridecanoate and sucrosemonotetradecanoate.

Another embodiment provides a method of treating or mitigating diseasesor conditions suitable for treatment with triptan compounds in a subjectin need thereof, said method comprising intranasally administering tosaid subject a pharmaceutical composition comprising a triptan, apharmaceutically acceptable vehicle and a mucosal permeation enhancer,wherein upon said administration, said composition provides a C_(max) ata time T_(max), ii) C_(max2) at a time T_(max2), iii) a C_(min) at atime of T_(min), and iv) a ratio of C_(max2) to AUC_(Tmin-inf), saidT_(min) being later than said T_(max) and earlier than said T_(max2),said C_(max) and said T_(max) being characteristic of subcutaneousadministration and said AUC_(Tmin-inf) being characteristic ofintranasal administration without said mucosal permeation enhancer.

In the above aspect, said T_(max) ranges from about 4.5 to about 15minutes.

In the above aspect, said composition provides a C_(max2) at a time ofT_(max2), said T_(max2) being later than said T_(max).

In the above aspect, said composition provides a C_(min) at a time ofT_(min), said T_(min) being later than said T_(max) and earlier thansaid T_(max2).

In the above aspect, wherein said mucosal permeation enhancer is alkylglycoside or saccharide alkyl ester.

In the above aspect, the said alkyl glycoside or saccharide alkyl esteris selected from (1-O-n-Dodecyl-β-D-Maltopyranoside), tridecylmaltoside, sucrose monododecanoate, sucrose monotridecanoate and sucrosemonotetradecanoate.

Specifically contemplated is pharmaceutical composition as describedherein, which provides AUC₀₋₂ ranging from about 22 to 160 ng·h/mL.

Specifically contemplated is pharmaceutical composition as describedherein, which provides AUC₀₋₆ ranging from about 25 to 160 ng·h/mL.

In one embodiment, each salt of sumatriptan, as defined above, isindividually contemplated.

In another embodiment, aqueous solution of a salt of the presentinvention adapted for intranasal administration can have a pH in therange of about 4 to about 8. In another embodiment, the pH of aqueoussolutions of the salt according to the invention for intranasaladministration will be about 4.5 to about 7.5.

In another embodiment, the pH of an aqueous solution of a citrate saltof sumatriptan according to the invention for intranasal administrationwill be about about 4.5 to about 6.5, such as about 5 to about 6.Adjustment of the pH value of aqueous solutions of the sumatriptan saltto be within a desired range is conveniently effected by addition of abase, such as an inorganic base, such as an alkali metal hydroxide,including sodium or potassium hydroxide.

The aqueous solutions of the present invention may be prepared bydissolving the drug in water containing corresponding acid. For example,In one embodiment, solution can be prepared by admixture of 1 molarequivalent of sumatriptan and about 0.2 to 0.5 molar equivalent ofconcentrated phosphoric acid, or 0.30 molar equivalent of concentratedphosphoric acid, in water.

In another embodiment, solution can be prepared by admixture of 1 molarequivalent of sumatriptan and about 0.3 to about 0.6 molar equivalent ofcitric acid monohydrate, or about 0.43 molar equivalent of citric acidmonohydrate, in water.

It will be appreciated that the precise therapeutic doses of the saltwill depend on the age and condition of the patient and the nature ofthe condition to be treated, and will be in the ultimate discretion ofthe attendant physician.

However, in general effective doses for the treatment of conditionsassociated with cephalic pain, for example acute treatment of migraine,will lie in the range of about 0.5 to 100 mg, or about 1 to 60 mg, orabout 2 to 40 mg of the active ingredient, per unit dose, which could beadministered in single or divided doses, for example, 1 to 4 times perday.

The salt of the present invention may conveniently be presented in unitdose form. A convenient unit dose formulation for intranasaladministration contains the active ingredient in an amount of about 0.5mg to 100 mg, or about 1 to 60 mg, or about 2 to 40 mg, which may beadministered into either one or both nostrils. In an embodiment, 2.5 mgto 25 mg of the active ingredient is administered in a single dose toone nostril.

A unit dose formulation may be provided as a single dose in a sealedunit, for example a vial of glass or plastic material which may befilled and sealed using conventional manufacturing techniques.Alternatively, a sealed vial of plastics material may be produced byform-fill-seal technology. In an embodiment, the vial and the componentsof the pharmaceutical formulation filled therein are heat stable. Thesealed vial may be sterilized, for example by autoclaving at 120° C. fornot less than 15 minutes, to provide a sterile unit dosage vial whichcan be assembled into a convenient delivery device prior to use. Inanother embodiment, the unit dose volume is 50 to 200 μL, for example100 μL.

General Process-I:

A salt of sumatriptan may be prepared by dissolving sumatriptan, or asalt or a physiologically acceptable solvate thereof, in a solution ofphosphoric acid or citric acid monohydrate. The process may be desirablycarried out in aqueous media, optionally in the presence of an organicsolvent such as an alcohol (for example, ethanol or isopropanol).Further, a salt of sumatriptan may be prepared by admixture of thesumatriptan base and phosphoric acid or citric acid monohydrate, inwater.

General Process-II:

A salt of sumatriptan may be prepared by dissolving sumatriptan or asalt or solvate thereof in a solution of maleic acid, acetic acid, orformic acid. The process may be desirably carried out in aqueous media,optionally in the presence of an organic solvent such as an alcohol (forexample, ethanol or isopropanol). Further, a salt of sumatriptan isprepared by admixture of sumatriptan base and formic acid, acetic acidor maleic acid, in water.

The pH of the product obtained is adjusted to about 4 to about 8, by theaddition of sodium hydroxide or phosphate buffer.

In an alternative aspect of the present invention provides apharmaceutical composition in a form adapted for intranasaladministration, comprising an aqueous solution of sumatriptan or aphysiologically acceptable salt or solvate thereof and an alkylglycosideor saccharide alkyl ester, wherein the solution has pH value in therange of about 4.5 to about 7.5.

Further alternative aspect of the present invention provides a methodfor the treatment of a mammal, including human being, suffering from orsusceptible to cephalic pain, in particular migraine, which comprisesintranasal administration of a pharmaceutical composition comprising anaqueous solution of sumatriptan or a physiologically acceptable salt orsolvate thereof and an alkylglycoside or saccharide alkyl ester, whereinthe solution has pH value in the range of about 5 to about 7.

Oral compositions may be associated with certain disadvantages in thetreatment of conditions associated with cephalic pain. For example, suchconditions, particularly migraine, are often accompanied by nausea whichmakes it difficult for a patient to take an oral composition. It is alsohighly desirable, particularly in the treatment of acute conditions,that pharmaceutical composition having high bioavailability and a rapidand consistent onset of action.

Rapid absorption can be achieved by parenteral administration(intravenous, subcutaneous, intraperitoneal, or intrarterial), but thismay be unacceptable to some patients, especially if the drug is to beself-administered. Intranasal administration represents a convenientalternative route for administration.

Intranasal formulations may generally be provided in liquid or in drypowder forms. Satisfactory intranasal formulations must be sufficientlystable, chemically and physically, to be consistently dispensed inaccurate metered doses, even after prolonged storage with potentialtemperature fluctuations of between 10 and 40° C. Accordingly, theactive ingredient must be compatible with the excipients used in theformulation and should not aggregate in a manner which would result in aloss of accurate dose delivery, for example by precipitation from aliquid formulation or by caking of a powder formulation. To maximizeretention of an intranasal formulation within the nasal passages of apatient after administration, particularly of a liquid formulation, itis desirable to deliver the unit dosage of active ingredient within arelatively small delivery volume, for example 50-200 μL, or 100 μL orless. This may necessitate the use of high concentrations of medicamentand highly soluble active ingredients are therefore advantageous.Clearly, an active ingredient must also be presented in a form which isreadily absorbed through the nasal mucosa but which is unassociated withany adverse effects such as irritancy.

Solutions of an active ingredient will generally be aqueous, for exampleprepared from water alone (for example sterile or pyrogen-free water),or water and a physiologically acceptable co-solvent (for exampleethanol, propylene glycol, and polyethylene glycols such as PEG 400).

Such solutions may additionally-contain other excipients such aspreservatives (for example benzalkonium chloride and phenylethylalcohol), buffering agents, isotonicity-adjusting agents (for examplesodium chloride), viscosity enhancing agents, absorption enhancers,flavoring agents (for example aromatic flavoring agents such as menthol,eucalyptol, camphor and methyl salicylate in amounts of about 0.001 to0.5% w/w) and sweetening agents (for example saccharin in amounts ofabout 0.01% w/w to about 10% w/w, or in the range of about 1 to 5% w/w).

Solutions are applied directly to the nasal cavity by conventionalmeans, for example with a dropper, pipette, or spray. The formulationsmay be provided in single- or multi-dose form. In the latter case, ameans of dose metering is desirably provided. In the case of a dropperor pipette, this may be achieved by the patient administering anappropriate, predetermined volume of the solution. In the case of aspray, this may be achieved, for example, by means of a meteringatomizing spray pump.

Intranasal administration may also be achieved by means of an aerosolformulation in which the compound is provided in a pressurized packagewith a suitable propellant such as a chlorofluorocarbon (CFC), forexample dichlorodifluoromethane, trichlorofluoromethane ordichlorotetrafluoroethane, a hydrofluorocarbon (HFC), for example1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, carbondioxide, or another suitable gas. The dose of drug may be controlled byprovision of a metering valve.

In an embodiment, the invention includes use of packaging materials suchas containers and closures of high-density polyethylene (HDPE),low-density polyethylene (LDPE) and or polypropylene and/or glass,glassine foil, aluminum pouches, and blisters or strips composed ofaluminum or high-density polypropylene, polyvinyl chloride,polyvinylidene dichloride, etc.

The following examples further describe certain specific aspects andembodiments of the present invention and demonstrate the practice andadvantages thereof. It is to be understood that the examples are givenby way of illustration only and are not intended to limit the scope ofthe invention in any manner.

Preparation of Citrate Salt of Sumatriptan:

Added 130.0 grams (0.4406 mol) of Sumatriptan base to 1300 mL of ethanolin a round bottomed flask and heated the mixture under refluxtemperature to get homogeneous solution. Added 97.2 grams (0.462 mol) ofcitric acid monohydrate and 1300 mL of ethanol solution to abovereaction mixture at reflux. Maintained the reaction mixture at refluxtemperature for 30 to 60 minutes. Cooled the reaction mixture to 25-35°C. and added 780 mL of Isopropanol and stirred for 15 to 30 minutes.Some gummy mass attached to the walls of the flask. Decanted solventcompletely and added 2600 mL of isopropanol to the gummy mass andstirred for 2 to 4 hours. Filtered the solid and washed with 650 mL ofIsopropanol. Added 2600 mL of Isopropanol to the wet solid and stirredfor 2 to 4 hours. Filtered the solid and washed with 650 mL ofIsopropanol. Dried the wet solid under reduced pressure at 50 to 60° C.till constant weight obtains. Yield: 126.5 g HPLC: 99.72%, Assay byHPLC: 67.2% (Sumatriptan base), Moisture content: 2.0%, Assay by HPLC:27.1% for Citric acid & 29.5% for Citric acid Monohydrate.

By following the similar methodology as described above other salts ofsumatriptan can be prepared.

General Process for the Preparation of Salt Compositions: ManufacturingProcess:

-   Step-i: An acid of corresponding salt was dissolved in water-   Step-ii: Sumatriptan was dissolved in the solution.-   Step-iii: Phosphate buffer was added and mixed well and pH was    checked and adjusted with sodium hydroxide (1N), if required.-   Step-iv: The solution was filtered through a membrane filter and the    pH was checked to maintain the pH range about 4 to about 8.-   Step-v: Alkyl saccharide was dissolved in the solution. The solution    was made to final volume with phosphate buffer and pH was again    checked.

Example-1: Preparation of ‘Citrate Salt of Sumatriptan’ CompositionProcedure:

-   Step-i: Preparation of Phosphate buffer:    -   0.2 grams of dibasic sodium phosphate & 10.0 grams of monobasic        potassium phosphate was dissolved in sufficient water to produce        1000 mL.-   Step-ii: Preparation of 1N Sodium hydroxide:    -   Dissolve 1.0 gram of Sodium hydroxide was dissolved in        sufficient water to produce 25 mL.-   Step-iii: Preparation of 5N citric acid monohydrate:    -   70.04 grams of citric acid monohydrate was dissolved in        sufficient quantity of purified water and the volume was made up        with purified water to 200 mL.-   Step-iv: The required quantity of citric acid monohydrate (5N)    solution was added to the required quantity of water and mixed well    to get a uniform mixture. To this was added the required quantity of    sumatriptan and the mixture was stirred to dissolve the drug.-   Step-v: The pH of solution obtained in Step-iv was checked and    required quantity of sodium hydroxide (1N) was added to it to adjust    the pH of the solution to 5.5±0.5.-   Step-vi: A required quantity of phosphate buffer was added to the    solution of Step-v and was mixed well. The pH was checked and when    if necessary was adjusted to the requisite value by adding a    required quantity of sodium hydroxide (1N).-   Step-vii: A required quantity of 1-O-n-Dodecyl-β-D-Maltopyranoside    was added to a solution of Step-vi and mixed well till it dissolved    completely. The volume was made up with phosphate buffer and the    resulting solution was mixed well.-   Step-viii: The solution of Step-vii was filtered through a membrane    filter by SS Filtration assembly.-   Step-ix: The required quantity of solution of Step-viii was filled    in a nasal spray device.

Qty/Unit dose (mg/100 μl) S. No. Ingredient For 5 mg For 10 mg For 15 mgFor 20 mg 1 Sumatriptan 5.00 mg 10.00 mg 15.00 mg 20.00 mg 2 Citric acidmonohydrate * 1.576 mg 3.152 mg 4.728 6.304 mg 3 1-O-n-Dodecyl-β-D- 0.20mg 0.20 mg 0.20 mg 0.20 mg Maltopyranoside 4 Sodium hydroxide q.s. toq.s. to q.s. to q.s. to adjust pH adjust pH adjust pH adjust pH 5.0-6.05.0-6.0 5.0-6.0 5.0-6.0 5 Purified water 20.000 μl 20.000 μl 20.000 μl20.000 μl 6 Phosphate Buffer ** q.s. to q.s. to q.s. to q.s. to 100 μl100 μl 100 μl 100 μl q.s.—quantum sufficient * To be used as (5N) Citricacid solution in purified water. ** Contains Dibasic sodium phosphateand Monobasic potassium phosphate and to be mixed in the ratio of 1:50in purified water for the preparation of Phosphate buffer.

Example-2: Preparation of ‘Phosphate Salt of Sumatriptan’ Composition

Pharmaceutical composition comprising phosphate salt of Sumatriptan isprepared by similar procedure as described in Example-1, with thefollowing quantities of the reacting materials.

Ingredient/Condition Quantity/Value Sumatriptan 20 mg1-O-n-Dodecyl-β-D-Maltopyranoside 0.2 mg Phosphoric acid 4.03 μL Citricacid monohydrate — Sodium hydroxide q.s. Water 20 μL Phosphate bufferq.s. to 100 μL pH 6.5-7.5

Examples 3-5: Preparation of ‘Formate, Acetate and Maleate Salts ofSumatriptan’ Composition

The compositions of Formate, Acetate and Maleate salt of Sumatriptancomposition can be prepared by following the procedure as described inExample-I by taking appropriate quantities of the reacting substancesand by maintaining appropriate suitable pH conditions.

Composi- Composi- Composi- tion of tion of tion of Exam- Exam- Exam- S.No Ingredients ple-3 ple-4 ple-5 1 Sumatriptan 20.00 mg 20.00 mg 20.00mg 2 Formic acid * 2.55 μl NA NA 3 Acetic acid ** NA 3.80 μl NA 4 Maleicacid *** NA NA 3.86 mg 5 1-O-n-Dodecyl-β-D- 0.2 mg 0.2 mg 0.2 mgMaltopyranoside 6 Phosphate buffer 100 μl 100 μl 100 μl pH observed forfinal 6.96 5.49 7.05 solution * To be used as (10N) Formic acid solutionin water. ** To be used as (10N) Acetic acid solution in water. *** Tobe used as (5N) Maleic acid solution in water.

Example-6: Sumatriptan Citrate Salt Composition

Composition comprising Sumatriptan Citrate salt was prepared byfollowing procedure:

-   Step-i: Preparation of Phosphate buffer: Dissolved 0.2 grams of    dibasic sodium phosphate & 10.0 grams of monobasic potassium    phosphate in sufficient water to produce 1000 mL.-   Step-ii: Preparation of 1N Sodium hydroxide: Dissolved 1.0 gram of    Sodium hydroxide in required quantity of water and dilute with water    to 25 mL.-   Step-iii: Added the required quantity of Sumatriptan-Citric acid    monohydrate complex to required quantity of water and mix well until    it dissolves.-   Step-iv: Checked the pH of solution of step-iv and added required    quantity of sodium hydroxide (1N) to it to adjust the pH of the    solution to 5.5±0.5.-   Step-v: Added required quantity of phosphate buffer to solution of    step-iv and mix well. Checked the pH and if necessary and added    required quantity of sodium hydroxide (1N) to adjust the pH of the    solution to 5.5±0.5.-   Step-vi: Added required quantity of n-Dodecyl-beta-D-Maltopyranoside    to solution of step-v and mixed well till it dissolves completely.    Made up the volume with phosphate buffer and mixed well.

Step- Qty/Unit dose vii: Item Name (Qty/100 μL) 1 Sumatriptan-Citricacid salt* 22.32 mg 2 n-Dodecyl-beta-D-Maltopyranoside 0.20 mg 3 Sodiumhydroxide q.s. to adjust pH 5.0-6.0 4 Purified water 20.00 μl 5Phosphate buffer ** q.s. to 100 μL

Example-7: Other Sumatriptan Salt Compositions

By taking appropriate Sumatriptan salt, pharmaceutical compositions canbe prepared by following the procedure as described in Example-6.

Example-8: Clinical Trials Data

Study-1:

4-way crossover study of intranasal administration of sulphate salt ofsumatriptan with Test-1, Test-2, Test-3 having the permeation enhancerin concentrations of 0.1%, 0.15%, 0.2% respectively and Imitrex® 20 mgas the reference product (Refer FIG. 4)

(Number of subjects completed study (n)=21).

Each drug solution (Test-1, Test-2, Test-3 and Reference) isadministered to 24 patients in a three-way crossover study, with awashout period between doses of at least 7 days, as a 100 microlitermetered nasal spray using standard metered nasal spray devices such asthose manufactured by Ing. Erich Pfeiffer GmbH, Radolfzell, Germany,Valois Pharma, Le Neubourg, France, or Becton Dickinson, New Jersey,USA. Blood samples are collected from each patient at the timedintervals, for example 0.08, 0.17, 0.25, 0.33, 0.42, 0.6, 0.67, 0.83, 1,2, 3, 4, 6, 8, 12, 24 hours.

Sample for Test-1:

Sulphate salt of Sumatriptan composition 20 mg Nasal spray (a finalsumatriptan concentration of 20 mg per 100 microliter spray and havingabout 0.1% of permeation enhancer (dodecyl maltoside)), manufactured byDr. Reddy's Laboratories Ltd., India.

Sample for Test-2:

Sulphate salt of Sumatriptan composition 20 mg Nasal spray (a finalsumatriptan concentration of 20 mg per 100 microliter spray and havingabout 0.15% of permeation enhancer (dodecyl maltoside)), manufactured byDr. Reddy's Laboratories Ltd., India.

Sample for Test-3:

Sulphate salt of Sumatriptan composition 20 mg Nasal spray (a finalsumatriptan concentration of 20 mg per 100 microliter spray and havingabout 0.2% of permeation enhancer (dodecyl maltoside)), manufactured byDr. Reddy's Laboratories Ltd., India.

REFERENCE

-   Imitrex® (Sumatriptan) nasal spray, 20 mg per 100 microliters),    manufactured by GlaxoSmithKline.

Example-9 Study-2:

3-way crossover study of intranasal administration of varioussumatriptan salts (phosphate, citrate and sulphate) having 0.2% of thepermeation enhancer (Refer FIG. 1, FIG. 2 and FIG. 3 respectively)

(Number of Subjects Completed Study (n)=15)

Each drug solution (phosphate, citrate and sulfate salt of sumatriptan)is administered to 18 patients in a three-way crossover study, with awashout period between doses of at least 8 days, as a 100 microlitermetered nasal spray using standard metered nasal spray devices such asthose manufactured by Ing. Erich Pfeiffer GmbH, Radolfzell, Germany,Valois Pharma, Le Neubourg, France, or Becton Dickinson, New Jersey,USA. Blood samples are collected from each patient at the timedintervals, for example 0.08, 0.17, 0.25, 0.33, 0.42, 0.6, 0.67, 0.83, 1,2, 3, 4, 6, 8, 12, 24 hours.

Phosphate salt of Sumatriptan composition 20 mg Nasal spray (a finalsumatriptan concentration of 20 mg per 100 microliter spray and havingabout 0.2% of permeation enhancer (dodecyl maltoside)), manufactured byDr. Reddy's Laboratories Ltd., India.

Citrate salt of Sumatriptan composition 20 mg Nasal spray (a finalsumatriptan concentration of 20 mg per 100 microliter spray and havingabout 0.2% of permeation enhancer (dodecyl maltoside)), manufactured byDr. Reddy's Laboratories Ltd., India.

Sulphate salt of Sumatriptan composition 20 mg Nasal spray (a finalsumatriptan concentration of 20 mg per 100 microliter spray and havingabout 0.2% of permeation enhancer (dodecyl maltoside)), manufactured byDr. Reddy's Laboratories Ltd., India.

Example-10 Study-3:

3-way crossover study of intranasal administration of sulphate salt ofsumatriptan with Test-1 having about 0.2% of permeation enhancer; Test-2without permeation enhancer and Imitrex® as the reference product

(Number of Subjects Completed Study (n)=15)

Each drug solution (Test-1, Test-2 and Reference samples) isadministered to 18 patients in a three-way crossover study, with awashout period between doses of at least 4 days, as a 100 microlitermetered nasal spray using standard metered nasal spray devices such asthose manufactured by Ing. Erich Pfeiffer GmbH, Radolfzell, Germany,Valois Pharma, Le Neubourg, France, or Becton Dickinson, New Jersey,USA. Blood samples are collected from each patient at the timedintervals, for example 0.08, 0.17, 0.25, 0.33, 0.42, 0.6, 0.67, 0.83, 1,2, 3, 4, 6, 8, 12, 24 hours.

Sample used in Test-1:

Sulfate salt of Sumatriptan composition 20 mg Nasal spray (a finalsumatriptan concentration of 20 mg per 100 microliter spray and havingabout 0.2% of permeation enhancer (dodecyl maltoside)), manufactured byDr. Reddy's Laboratories Ltd., India.

Sample used in Test-2:

Sulfate salt of Sumatriptan composition 20 mg Nasal spray (a finalsumatriptan concentration of 20 mg per 100 microliter spray and withoutpermeation enhancer), manufactured by Dr. Reddy's Laboratories Ltd.,India.

REFERENCE

-   Imitrex® (Sumatriptan) nasal spray, 20 mg per 100 microliters),    manufactured by GlaxoSmithKline,

TABLE 1 Area under the plasma concentration versus time curve from time0 to infinity (AUC_(0-inf)) AUC_(0-inf) (ng · h/mL) Study2 Study2 Study2Study3 (Sulphate Study1 (Phosphate (Citrate Statistics (0.2%) salt)(0.2%) salt) salt) Arithmetic 114.70 135.52 125.18 107.67 142.57 MeanStandard 52.98 48.78 46.72 25.03 45.83 Deviation Max 222.44 201.58201.46 169.32 258.86 Median 109.04 130.73 117.94 108.22 136.85 Min 33.4550.91 14.81 63.08 80.16 G. Mean 101.68 125.64 112.78 104.98 136.27 CV %46.19 36.0 37.33 23.25 32.15

TABLE 2 Peak plasma concentration for sumatriptan (C_(max)) C_(max)(ng/mL) Study2 Study2 Study2 Study3 (Sulphate Study1 (Phosphate (CitrateStatistics (0.2%) salt) (0.2%) salt) salt) Arithmetic 60.50 84.98 83.6944.78 85.30 Mean Standard 31.93 57.79 46.44 17.18 34.56 Deviation Max110.88 213.11 173.43 81.22 186.33 Median 67.48 85.30 78.35 40.26 86.65Min 8.44 15.62 5.95 22.69 48.62 G. Mean 48.65 67.68 67.54 41.96 79.95 CV% 55.05 68.01 55.50 38.37 40.52

TABLE 3 Time to peak plasma concentration for sumatriptan (T_(max))T_(max)(h) Study2 Study2 Study2 Study3 (sulphate Study1 (Phosphate(Citrate Statistics (0.2%) salt) (0.2%) salt) salt) Arithmetic 0.21 0.240.21 0.43 0.161 Mean Standard 0.13 0.28 0.18 0.55 0.05 Deviation Maximum0.66 1.25 1.00 0.25 0.25 Median 0.167 0.167 0.167 0.167 0.167 Minimum0.083 0.083 0.083 0.083 0.083 CV % 62.97 114.74 84.84 127.76 30.76

TABLE 4 Area under the plasma concentration versus time curve from time0 to Tmax (AUC_(0-Tmax)) AUC_(0-Tmax) (ng · h/mL) Study2 Study2 Study2Study3 Study3 (Sulphate Study1 (Phosphate (Citrate (Imitrex Statistics(0.2%) salt) (0.2%) salt) salt) 20 mg) G. Mean 4.51 5.99 6.22 3.39 12.9913.54 Arithmetic 6.05 7.93 7.95 3.72 13.63 14.36 Mean 95% CI 4.3-7.84.9-11.0 6.0-9.9 3.0-4.5 11.6-15.7 12.2-16.5

TABLE 5 Ratio of C_(max) to AUC_(0-inf) (C_(max)/AUC_(0-inf))C_(max)/AUC_(0-inf) Study2 Study2 Study2 Study3 (Sulphate Study1(Phosphate (Citrate Statistics (0.2%) salt) (0.2%) salt) salt) G. Mean0.47 0.53 0.59 0.18 0.47 Arithmetic 0.52 0.62 0.66 0.41 0.59 Mean 95% CI0.5-0.54 0.5-0.71 0.6-0.71 0.37-0.44 0.57-0.62

TABLE 6 Area under the plasma concentration versus time curve from time0 to 2 hours (AUC₀₋₂) AUC₀₋₂ (ng · h/mL) Study2 Study2 Study2 Statistics(Sulphate salt) (Phosphate salt) (Citrate salt) A. Mean 63.81 44.9768.07 Std. Dev 27.92 11.11 29.59 Max 116.49 60.80 156.13 Median 69.0846.57 61.11 Min 22.05 25.79 38.39 G. Mean 57.16 43.58 63.49 CV % 43.7524.72 43.48

TABLE 7 Area under the plasma concentration versus time curve from time0 to 6 hours (AUC₀₋₆) AUC₀₋₆ (ng · h/mL) Study2 Study2 Study2 Statistics(Sulphate salt) (Phosphate salt) (Citrate salt) A. Mean 68.08 88.9844.97 Std. Dev 29.60 21.87 11.12 Max 156.13 142.27 60.80 Median 61.1291.46 46.58 Min 38.39 55.32 25.79 G. Mean 63.50 86.50 43.59 CV % 43.4824.58 24.72

1.-34. (canceled)
 35. A pharmaceutical composition for intranasaladministration comprising a triptan, a pharmaceutically acceptablevehicle and a mucosal permeation enhancer, wherein upon saidadministration said composition provides a T_(max) substantiallyequivalent to subcutaneous administration of said triptan.
 36. Thepharmaceutical composition of claim 35, wherein said mucosal permeationenhancer is not a cyclodextrin.
 37. The pharmaceutical composition ofclaim 35, wherein said mucosal permeation enhancer is present in aconcentration of from about 0.05% to about 3.0%
 39. The pharmaceuticalcomposition of claim 35, wherein said T_(max) ranges from about 4 toabout 15 minutes.
 43. The pharmaceutical composition of claim 35,wherein said mucosal permeation enhancer is alkyl glycoside orsaccharide alkyl ester.
 44. The pharmaceutical composition of claim 43,wherein the said alkyl glycoside or saccharide alkyl ester is selectedfrom 1-O-n-Dodecyl-β-D-Maltopyranoside, tridecyl maltoside, sucrosemonododecanoate, sucrose monotridecanoate, and sucrosemonotetradecanoate.
 45. The pharmaceutical composition of claim 44,wherein said triptan compound is a sumatriptan, a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvatethereof. 46.-52. (canceled)
 53. A method of treating diseases andconditions suitable for treatment with triptan compounds in a subject inneed thereof, said method comprising intranasally administering to saidsubject a pharmaceutical composition comprising a triptan, apharmaceutically acceptable vehicle and a mucosal permeation enhancer,wherein upon said administration, said composition provides a T_(max)equivalent to subcutaneous administration of said triptan.
 54. Themethod of claim 53, wherein said T_(max) ranges from about 4 to about 15minutes.
 58. The method of claim 53, wherein said mucosal permeationenhancer is alkyl glycoside or saccharide alkyl ester.
 59. The method ofclaim 58, wherein the said alkyl glycoside or saccharide alkyl ester isselected from 1-O-n-Dodecyl-β-D-Maltopyranoside, tridecyl maltoside,sucrose monododecanoate, sucrose monotridecanoate, and sucrosemonotetradecanoate. 60.-71. (canceled)
 72. The method of claim 53,wherein said triptan compound is a sumatriptan, a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvatethereof.
 73. A pharmaceutical composition comprising: an aqueousbuffered solution comprising a salt of sumatriptan or a physiologicallyacceptable solvate thereof; and means for enhancing penetration of adrug via mucosal membrane.
 74. The pharmaceutical composition of claim73, wherein said means for enhancing penetration of a drug via mucosalmembrane comprises alkyl glycoside or saccharide ester.
 75. Thepharmaceutical composition of claim 74, wherein said alkyl glycoside orsaccharide ester is selected from 1-O-n-Dodecyl-β-D-Maltopyranoside,tridecyl maltoside, sucrose monododecanoate, sucrose monotridecanoate,and sucrose monotetradecanoate.
 76. The pharmaceutical composition ofclaim 74, wherein said alkyl glycoside or saccharide alkyl ester ispresent in a concentration of from about 0.05% to about 3.0%.
 77. Thepharmaceutical composition of claim 73, wherein said pharmaceuticalcomposition provides Tmax value of less than 30 minutes upon intranasaladministration.
 78. The pharmaceutical composition of claim 73, whereinsaid salt of sumatriptan is selected from sulfate, phosphate, citrate,maleate, formate, acetate, or succinate.
 79. The pharmaceuticalcomposition of claim 73, wherein said pharmaceutical compositionprovides a T_(max) substantially equivalent to subcutaneousadministration of said triptan.
 80. The pharmaceutical composition ofclaim 73, wherein said pharmaceutical composition provides a T_(max)value of less than about 30 minutes.